DECREASING TRANSMURAL DISPERSION OF VENTRICULAR ACTION POTENTIAL REPOLARIZATION WITH MULTICHANNEL PHARMACOLOGY

Dispersion of repolarization results from a non-homogeneous recovery of excitability in cardiac tissue, and it is an important factor in arrhythmogenesis because it could lead to the initiation and maintenance of a variety of arrhythmias. Antiarrhythmic agents that prolong APD by selectively blocking specific ion channels (like I _Kr ) often increase dispersion of repolarization, which could result in a pro-arrhythmic risk. In this report, using computer models of the action potential of human epicardial and mid-myocardial myocytes, we have identified two strategies to prolong APD while reducing transmural dispersion of repolarization. The first strategy, which involves blocking several depolarizing and repolarizing ion channels (I _NaL , I _CaL , I _Kr and I _NaCa ), can reduce the transmural APD dispersion by about 20%. The second strategy, which involves the use of a combination of ion channel blockers and activators, results in a stronger reduction in transmural dispersion of repolarization than using only ion channel blockers. Enhancing I _Ks and blocking I _Kr can reduce transmural APD dispersion by about 70%. Our results suggest that a multichannel pharmacology strategy (as opposed to a single channel strategy), possibly using ion channel blockers and activators, can be effective at increasing APD while minimizing dispersion of repolarization.